Tolep - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Oxcarbazepine

TOLEP 300 mg tablets
TOLEP 600 mg tablets

Indications Why is Tolep used? What is it for?

Pharmacotherapeutic group

Antiepileptic, derivative of carboxamide.

Therapeutic indications

Tolep is indicated for the treatment of partial seizures with or without secondary generalized tonic clonic seizures.

Tolep is indicated for use in both monotherapy and adjunct therapy in adults and children 6 years of age and older.

Contraindications When Tolep should not be used

Hypersensitivity to the active substance or to any of the excipients.

Precautions for use What you need to know before taking Tolep

Tolep should only be administered under medical supervision.

Hypersensitivity

In the post-marketing period, class I (immediate) hypersensitivity reactions including rash, pruritus, urticaria, angioedema and cases of anaphylaxis have been reported. Cases of anaphylaxis and angioedema affecting the larynx, glottis, lips and eyelids have been reported after taking the first or subsequent doses of Tolep. If these reactions occur in a patient after treatment with Tolep, they should discontinue administration of Tolep and alternative therapy should be initiated.

Patients who have experienced hypersensitivity reactions to carbamazepine should be informed that approximately 25-30% of the same patients may re-occur similar reactions (eg severe skin reactions) after taking Tolep (see "Undesirable effects").

Hypersensitivity reactions, including multi-organ hypersensitivity reactions, may also occur in patients who have not had previous episodes of carbamazepine hypersensitivity. These reactions can affect the skin, liver, blood and lymphatic system or other organs, either individually or simultaneously in the case of a systemic reaction (see "Undesirable effects"). In general, if signs and symptoms suggesting hypersensitivity reactions occur, Tolep administration should be stopped immediately.

Dermatological effects

In very rare cases, severe dermatological reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome) and erythema multiforme, have been reported in association with the use of Tolep. Patients with severe dermatological reactions may need hospitalization, as these conditions can be life-threatening and very rarely fatal. Episodes of this type associated with the use of Tolep have been reported in both children and adults. The mean time to onset was 19 days. Several isolated cases of recurrence of severe skin reactions have been reported when treatment with Tolep was restarted. Patients on Tolep therapy who develop a skin reaction should be promptly evaluated and treatment with Tolep should be stopped immediately unless the rash is clearly unrelated to the drug. If treatment is discontinued, consideration should be given to replacing Tolep with another antiepileptic medicinal product to avoid withdrawal attacks. Tolep must not be re-administered in patients who have discontinued treatment due to hypersensitivity reactions (see "Contraindications"). .

The risk of severe skin reactions in Han Chinese or Thai patients associated with carbamazepine or chemically related substances can be predicted by testing a blood sample from these patients. Your doctor should be able to advise if blood testing is needed before taking oxcarbazepine.

Risk of worsening of seizures

The risk of worsening of seizures has been reported during treatment with oxcarbazepine. The risk of worsening seizures has been observed mainly in children but can also occur in adults. In case of worsening of the seizures, Tolep therapy should be discontinued.

Hyponatremia

In patients with pre-existing renal dysfunction associated with low sodium levels (e.g. syndrome of inappropriate ADH secretion) or in patients treated concomitantly with drugs that lower sodium levels (e.g. diuretics, desmopressin, molecules associated with inappropriate ADH secretion) as with non-steroidal anti-inflammatory drugs (e.g. indomethacin), blood sodium levels should be measured before starting therapy, after approximately two weeks and thereafter at monthly intervals within the first three months of therapy, or as judged by the physician. These risk factors can mainly affect elderly patients. Patients already on Tolep who start treatment with drugs that lower sodium levels should undergo the same checks on blood sodium levels. In general, if symptoms suggesting hyponatremia (too low blood sodium levels; see "Side effects") occur during Tolep therapy, your doctor may decide to take blood sodium measurements. For other patients these tests may be part of the normal laboratory controls.

All patients with heart failure and secondary heart failure should have their weight checked regularly to make sure fluid retention is not occurring. In the event of fluid retention or worsening heart conditions, blood sodium levels should be checked. If hyponatremia is observed, it may be helpful to reduce the fluids consumed. Patients with pre-existing conduction disturbances (e.g. atrioventricular block, arrhythmia) should be closely monitored.

Hypothyroidism

Hypothyroidism is a very rare adverse reaction to oxcarbazepine. Considering the importance of thyroid hormones in the development of children after birth, it is recommended that thyroid function be checked prior to initiating treatment with Tolep in pediatric patients. In pediatric patients, monitoring of thyroid function is recommended during treatment with Tolep. .

Liver function

Very rare episodes of hepatitis have been reported, which resolved favorably in most cases. When a liver effect is suspected, hepatic function should be monitored and discontinuation of Tolep therapy considered. Caution is advised when administering Tolep to patients with severe hepatic impairment (see "Dose, method and time of administration").

Renal function

In patients with renal impairment (creatinine clearance less than 30 ml / min) caution should be exercised during treatment with Tolep particularly with regard to starting dose and dose titration (see "Dose, method and time of administration" ).

Hematological effects

Post marketing very rare cases of agranulocytosis, aplastic anemia and pancytopenia have been reported in patients treated with Tolep (see "Undesirable effects"). Discontinuation of treatment should be considered if signs of significant bone marrow depression occur.

Hormonal contraceptives

Patients of childbearing potential should be advised that concomitant use of Tolep and hormonal contraceptives may cancel the effect of the latter (see "Interactions"). It is recommended that alternative non-hormonal contraceptive methods be used during Tolep therapy.

Alcohol

Extreme caution is required if alcoholic beverages are consumed while taking Tolep due to the possible additive sedative effect.

Suicidal ideation and behavior

A small number of patients being treated with antiepileptic drugs such as Tolep have developed thoughts of self-harm or suicide. Anytime such thoughts arise, contact your doctor immediately.

Discontinuation of treatment

As with other antiepileptic drugs, Tolep treatment should be discontinued gradually to minimize the risk of increased seizure frequency.

Interactions Which drugs or foods can modify the effect of Tolep

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, even those without a prescription.

Potential interactions have been observed between Tolep and other antiepileptic drugs such as carbamazepine, phenobarbital, phenytoin, valproic acid and lamotrigine. When one or more antiepileptic drugs are co-administered with oxcarbazepine, cautious dose adjustment and / or monitoring of plasma levels may be necessary as appropriate, especially in pediatric patients concomitantly treated with lamotrigine. Concomitant therapy of Tolep and lamotrigine has been associated with an increased risk of adverse events (nausea, somnolence, dizziness and headache).

Tolep has been shown to affect the two components of an oral contraceptive, ethinylestradiol and levonorgestrel. Therefore, concomitant use of Tolep and hormonal contraceptives may render the latter ineffective (see "Precautions for use"). Other methods of contraception, other than hormonal ones, must be considered.

Interactions are possible between Tolep and immunosuppressants (eg cyclosporine, tacrolimus).

An interaction between oxcarbazepine and MAO inhibitors is theoretically possible, based on a structural relationship between oxcarbazepine and tricyclic antidepressants. Patients on tricyclic antidepressants were included in clinical trials and no clinically significant interactions were observed. Oxcarbazepine administration and lithium can cause increased neurotoxicity.

Upon discontinuation of Tolep therapy, dose reduction of concomitant medicinal products may be required after appropriate clinical evaluation and / or plasma level monitoring.

Tolep has been shown not to interfere with warfarin, viloxazine, cimetidine, erythromycin and dextropropoxyphene.

Warnings It is important to know that:

Pregnancy

Ask your doctor or pharmacist for advice before taking any medicine. Risks associated with epilepsy and antiepileptic medicinal products in general Patients who may become pregnant or who are of childbearing age should be given specialist advice.

The need for antiepileptic treatment should be re-evaluated when the patient plans to become pregnant.

It has been shown that the incidence of malformations is two to three times higher in those born to women with epilepsy than at a frequency of approximately 3% in the general population.

Those born to epileptic women are known to be more prone to developmental disorders, including malformations. Data from a limited number of pregnancies indicate that oxcarbazepine can cause serious birth defects when administered during pregnancy.

An increase in malformations with polytherapy has been observed in the treated population, however it has not been clarified to what extent the treatment is responsible for the disease. Furthermore, effective antiepileptic therapy should not be interrupted, as the aggravation of the disease is harmful to both the mother and the fetus.

Taking all this into consideration:

  • If patients taking Tolep become pregnant or plan to become pregnant, or if they need to start treatment with Tolep during pregnancy, the potential benefits of the medicine should be carefully weighed against the potential risk of fetal malformations. This is especially important during the first three months of pregnancy.
  • The lowest effective doses should be administered.
  • In women of childbearing potential, Tolep should be given as monotherapy whenever possible.
  • Patients should be advised that the risk of malformations may increase, and should be able to undergo prenatal screening.
  • During pregnancy, effective antiepileptic therapy with oxcarbazepine should not be discontinued, as worsening of the disease is harmful to both the mother and the fetus.

Monitoring and prevention

Antiepileptic drugs can contribute to folic acid deficiency, one of the possible factors responsible for fetal abnormalities. Supplemental administration of folic acid is recommended before and during pregnancy. Since the efficacy of this supplementary administration is not proven, the desirability of a specific prenatal diagnosis may also be considered in women on supplementary treatment with folic acid.

Due to the physiological changes that occur, plasma levels of the active metabolite of oxcarbazepine (the monohydroxylated derivative, MHD) may gradually decrease during pregnancy. Therefore, in women undergoing treatment with Tolep during pregnancy, it is recommended that the clinical response be closely monitored and the monitoring of plasma MHD concentrations should be considered to ensure adequate control of seizures during pregnancy. . Monitoring of plasma MHD concentrations may also be considered after delivery, especially if drug doses have been increased during pregnancy.

In the newborn

Bleeding disorders caused by antiepileptic drugs have been reported in newborns. As a precaution, vitamin K1 should be given for preventive purposes during the last weeks of pregnancy, and subsequently to newborns.

Feeding time

Oxcarbazepine and its active metabolite (MHD) are excreted in breast milk. Effects on infants exposed in this way to Tolep are unknown. Therefore Tolep should not be taken during breastfeeding.

Women of childbearing age and contraceptive measures

Women of childbearing potential should be advised of the need to use highly effective methods of contraception (preferably non-hormonal, such as intrauterine implants) during treatment with Tolep. Taking Tolep may cancel the therapeutic effect of ethinylestradiol and levonorgestrel-based oral contraceptives (see "Interactions" and "Precautions for use").

Fertility

There are no human data relating to fertility.

Effects on ability to drive and use machines

Adverse reactions such as dizziness, somnolence, ataxia, diplopia, blurred vision, visual disturbances, hyponatremia, disturbance of consciousness have been reported with the use of oxcarbazepine (for the complete list of adverse reactions see "Undesirable effects"), especially at the start of treatment or when making dose adjustments (more frequently during the titration phase). Patients should therefore exercise due caution when driving and using machines.

Dosage and method of use How to use Tolep: Dosage

As monotherapy and as adjunct therapy, Tolep treatment should be initiated by administering a clinically effective dose divided into two administrations. The dose can be increased according to the patient's clinical response. When Tolep is used to replace other antiepileptic medicinal products, the dose of the combination antiepileptic medicinal products should be gradually reduced when initiating therapy with Tolep. In add-on therapy, as the total load of antiepileptic medicinal products on the patient is increased, it may be necessary to reduce the dose of the other combination antiepileptics and / or to increase the dose of Tolep more slowly (see section "Precautions for use").

Adults

Monotherapy

Recommended starting dose

Treatment with Tolep should start with a dose of 600 mg / day (8-10 mg / kg / day) divided into two doses.

Maintenance dose

If clinically indicated, the dose may be increased in maximum increments of 600 mg / day at approximately weekly intervals from the starting dose until desired clinical response is achieved. Therapeutic effects are observed at doses between 600 mg / day and 2400 mg / day.

Maximum recommended dose

In a controlled hospital setting, dose increases up to 2400 mg / day have been made over 48 hours.

Adjunct therapy

Recommended starting dose

Treatment with Tolep should start with a dose of 600 mg / day (8-10 mg / kg / day) divided into two doses.

Maintenance dose

If clinically indicated, the dose may be increased in maximum increments of 600 mg / day at approximately weekly intervals starting with the starting dose until desired clinical response is achieved. Therapeutic effects are observed at doses between 600 mg / day and 2400 mg / day.

Maximum recommended dose

Daily doses ranging from 600 to 2400 mg / day were effective, although most patients were unable to tolerate the 2400 mg / day dose without concomitantly reducing other antiepileptic medicinal products, mainly due to the occurrence of adverse events associated with the drug. of the Central Nervous System. Daily doses above 2400 mg / day have not been systematically evaluated in clinical studies.

Elderly patients (65 years of age or older)

No special dosing recommendations are necessary in elderly patients as therapeutic doses are individually adjusted. Dosage adjustments are recommended in elderly patients with renal impairment (creatinine clearance less than 30 ml / min) (see section "Patients with renal impairment"). Close monitoring of sodium levels is recommended in patients at risk of hyponatremia (see "Precautions for use").

Patients with hepatic impairment

No dosage adjustment is required for patients with mild to moderate hepatic impairment. Tolep has not been studied in patients with severe hepatic impairment, therefore caution is recommended when administering Tolep to these patients.

Patients with renal impairment

In patients with renal impairment (creatinine clearance less than 30 ml / min), Tolep therapy should be started with half the usual starting dose (300 mg / day) and increased at least weekly intervals until desired clinical response is achieved (see "Precautions for use"). Increasing the dose in patients with renal impairment may require closer observation.

Children

Recommended starting dose

As monotherapy and as adjunct therapy, treatment with Tolep should start with a dose of 8-10 mg / kg / day, divided into two administrations.

Maintenance dose

A maintenance dose of 30-46 mg / kg / day, achieved over two weeks, has been shown to be effective and well tolerated in children. Therapeutic effects were observed at a mean maintenance dose of approximately 30 mg / kg. / day.

Maximum recommended dose

If clinically indicated, the dose may be increased in maximum increments of 10 mg / kg / day at approximately weekly intervals starting from the starting dose up to the maximum dose of 46 mg / kg / day to achieve the desired clinical response.

Tolep is indicated for use in children 6 years of age and older. Tolep is not recommended in children below 6 years of age as safety and efficacy have not been adequately demonstrated.

All the recommendations described above (adults, elderly and children) refer to the doses studied in clinical studies in all age groups. However, it may be decided, if appropriate, to initiate therapy with lower doses.

Method of administration

The tablets have a score line and can be cut in half to make them easier to swallow. However, the tablet cannot be divided into equal doses.

Tolep can be taken with or without meals.

Therapeutic monitoring

The therapeutic effect of oxcarbazepine is mainly exerted through its active metabolite 10-monohydroxy-derivative (MHD). Routine monitoring of oxcarbazepine or MHD plasma levels is not warranted. However, monitoring of MHD plasma levels can be taken into consideration. consideration during Tolep therapy to rule out non-adherence to treatment, or in situations where alteration in MHD clearance is to be expected, including the following:

  • changes in renal function (see "Patients with renal impairment")
  • pregnancy (see "Special Warnings - Pregnancy")
  • concomitant use of medicinal products that have an inductive effect on liver enzymes (see "Interactions").
  • pediatric and geriatric age

If any of these situations occur, the dose of Tolep can be adjusted (based on plasma levels measured 2-4 hours after dosing) to maintain peak MHD plasma levels <35 mg / l.

Overdose What to do if you have taken too much Tolep

Isolated cases of overdose have been reported. The maximum dose taken was approximately 24,000 mg.

Signs and symptoms

Hydro-electrolyte balance: hyponatremia

Eye disorders: diplopia, miosis, blurred vision

Gastrointestinal disorders: nausea, vomiting, hyperkinesis

General disorders and administration site conditions: asthenia

Investigations: respiratory rate depression, QTc interval prolongation

Nervous system disorders: drowsiness and somnolence, dizziness, ataxia, nystagmus, tremor, coordination disturbances (abnormal coordination), convulsions, headache, coma, unconsciousness, dyskinesia

Psychiatric disorders: aggression, agitation, confusional state

Vascular disorders: hypotension

Respiratory, thoracic and mediastinal disorders: dyspnoea.

Treatment

There is no specific antidote. Patients with symptoms of poisoning due to an overdose of Tolep should be treated with appropriate symptomatic and supportive therapy, and the drug should optionally be removed by gastric lavage or inactivated by administration of activated charcoal.

In case of accidental ingestion / intake of an excessive dose of Tolep, notify your doctor immediately or go to the nearest hospital.

Side Effects What are the side effects of Tolep

Like all medicines, Tolep can cause side effects, although not everybody gets them.

The most commonly reported adverse reactions are somnolence, headache, dizziness, diplopia, nausea, vomiting and fatigue, which occurred in more than 10% of patients.

The undesirable effects are listed below divided by type and frequency. Within each frequency class, undesirable effects are reported in descending order of severity.

Disorders of the blood and lymphatic system

  • Uncommon: leukopenia.
  • Very rare: thrombocytopenia
  • Not known: bone marrow depression, aplastic anemia, agranulocytosis, pancytopenia, neutropenia.

Disorders of the immune system

  • Very rare: hypersensitivity (including multi-organ hypersensitivity) characterized by rash, fever. Other organs or systems may be affected, such as the blood and lymphatic system (e.g. eosinophilia, thrombocytopenia, leukopenia, lymphadenopathy, splenomegaly), the liver (e.g. abnormal liver function test results, hepatitis), muscles and joints (e.g. joint swelling, myalgia, arthralgia), the nervous system (e.g. hepatic encephalopathy), the kidneys (e.g. proteinuria, interstitial nephritis, renal failure), the lungs (e.g. dyspnoea, pulmonary edema, asthma, bronchospasm, interstitial lung disease) , angioedema.
  • Not known: anaphylactic reactions.

Endocrine pathologies

  • Not known: hypothyroidism.

Metabolism and nutrition disorders

  • Common: hyponatremia.
  • Very rare: Hyponatremia * associated with signs and symptoms such as seizures, confusion, altered consciousness, encephalopathy, visual disturbances (e.g. blurred vision), vomiting, nausea, folic acid deficiency

Psychiatric disorders

  • Common: confusional state, depression, apathy, agitation (e.g. nervousness), emotional frailty.

Nervous system disorders

  • Very common: somnolence, headache, dizziness.
  • Common: ataxia, tremor, nystagmus, disturbed concentration, amnesia.

Eye disorders

  • Very common: diplopia.
  • Common: blurred vision, visual disturbances.

Ear and labyrinth disorders

  • Common: dizziness

Cardiac pathologies

  • Very rare: arrhythmias, atrioventricular block.

Vascular pathologies

  • Not known: hypertension.

Gastrointestinal disorders

  • Very common: nausea, vomiting.
  • Common: diarrhea, constipation, abdominal pain.
  • Very rare: pancreatitis and / or increased lipase and / or amylase

Hepatobiliary disorders

  • Very rare: hepatitis.

Skin and subcutaneous tissue disorders

  • Common: rash, alopecia, acne.
  • Uncommon: urticaria.
  • Very rare: angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), erythema multiforme (see "Precautions for use").

Musculoskeletal and connective tissue disorders

  • Very rare: systemic lupus erythematosus

General disorders and administration site conditions

  • Very common: fatigue. - Common: asthenia.

Diagnostic tests

  • Uncommon: elevated liver enzyme values, elevated blood alkaline phosphatase values.
  • Very rare: increase in amylase values, increase in lipase values.
  • Not known: decrease in T4 levels

* Clinically significant hyponatremia (serum sodium sodium

Adverse reactions from spontaneous reports and literature (frequency not known)

The following adverse reactions derive from post-marketing experience with Tolep and refer to spontaneous reports and cases described in the literature. As these reactions arise spontaneously from a population of uncertain size, it is not possible to estimate with certainty the frequency which is therefore indicated. as “not known.” Adverse reactions are listed by MedDRA system organ class. Within each class, adverse reactions are listed in order of decreasing severity.

Disorders of the immune system

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS).

Metabolism and nutrition disorders

Syndrome of inappropriate ADH secretion with signs and symptoms such as lethargy, nausea, dizziness, decreased serum (blood) osmolality, vomiting, headache, confusion or other neurological signs and symptoms.

Skin and subcutaneous tissue disorders

Acute Generalized Exanthematous Pustulosis (AGEP).

Injury, poisoning and procedural complications

Falls.

Nervous system disorders

Speech disturbances (including dysarthria), more frequent during the titration phase. Musculoskeletal and connective tissue disorders Cases of bone disease including osteopenia and osteoporosis (thinning of the bones) and fractures have been reported. Contact your doctor or pharmacist if you have been on antiepileptic medication for a long time, or if you have a history of osteoporosis, or if you are taking steroids.

Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the website http://www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Expiry: see the expiry date printed on the package

The expiry date refers to the product in intact and correctly stored packaging.

Warning: do not use the medicine after the expiry date shown on the package

This medicine does not require any special storage conditions.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Keep this medicine out of the sight and reach of children

Composition and pharmaceutical form

Composition

Each 300 mg divisible tablet contains: 300 mg oxcarbazepine.

Each 600 mg divisible tablet contains: 600 mg oxcarbazepine.

Excipients: anhydrous colloidal silica; microcrystalline cellulose; hypromellose; red iron oxide; yellow iron oxide; magnesium stearate; carmellose sodium.

Pharmaceutical form and content

Tablets

Box of 50 divisible tablets of 300 mg.

Box of 50 divisible tablets of 600 mg.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Tolep can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the primary packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER CIO 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

TOLEP TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 300 mg divisible tablet contains:

Oxcarbazepine 300 mg

Each 600 mg divisible tablet contains:

Oxcarbazepine 600 mg

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Tablets.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Epilepsy

- partial seizures with or without secondary generalization

- generalized tonic-clonic seizures.

04.2 Posology and method of administration

Dosage

Treatment with Tolep, whether administered as mono or polypharmacy, should be started gradually and the dosage should be adapted to the needs of the individual patient.

Adults

Monotherapy: the recommended starting dose is 300 mg per day, the dosage can be gradually increased until the best response is obtained, usually around 600-1200 mg / day.

Polytherapy (in patients with not well controlled epilepsy or in cases refractory to therapy): the recommended starting dose is 300 mg per day, the dosage can be gradually increased until the best response is obtained. The maintenance dose varies between 900 and 3000 mg / day.

Children

Experience with Tolep in children is limited and there is no experience in children under 3 years of age.

Furthermore, since it is difficult to customize the dosage with the available tablets and divide the daily dose into 2-3 times, the use of Tolep in pediatric age is not recommended. However, the use of the product in children under 3 years of age should be avoided.

Patients with hepatic insufficiency

No dosage adjustment is required for patients with mild to moderate hepatic impairment. Tolep has not been studied in patients with severe hepatic impairment, therefore caution is recommended when administering Tolep to these patients.

Patients with renal insufficiency

In patients with renal insufficiency (creatinine clearance less than 30 ml / min) the dosage of Tolep should be carefully established and the dose increased at least weekly until the desired clinical response is achieved.

Administration

In general, Tolep should be given 3 times a day, but when possible it should be given twice a day. The tablets can be taken during or after meals with some liquid.

04.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

04.4 Special warnings and appropriate precautions for use

Hypersensitivity

In the post-marketing period, class I (immediate) hypersensitivity reactions including rash, pruritus, urticaria, angioedema and cases of anaphylaxis have been reported. Cases of anaphylaxis and angioedema affecting the larynx, glottis, lips and eyelids have been reported after taking the first or subsequent doses of Tolep. If these reactions occur in a patient after treatment with Tolep, they should discontinue administration of Tolep and alternative therapy should be initiated.

Patients who have experienced hypersensitivity reactions to carbamazepine should be informed that approximately 25-30% of the same patients may experience similar reactions (eg severe skin reactions) after taking Tolep (see section 4.8).

Hypersensitivity reactions, including multi-organ hypersensitivity reactions, may also occur in patients who have not had previous episodes of carbamazepine hypersensitivity. These reactions may affect the skin, liver, blood and lymphatic system or other organs, either individually or simultaneously in the case of a systemic reaction (see section 4.8). In general, if signs and symptoms suggesting hypersensitivity reactions occur, Tolep administration should be stopped immediately.

Dermatological effects

In very rare cases, severe dermatological reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome) and erythema multiforme, have been reported in association with the use of Tolep. Patients with severe dermatological reactions may need hospitalization, as these conditions can be life-threatening and very rarely fatal. Episodes of this type associated with the use of Tolep have been reported in both children and adults. The mean time to onset was 19 days. Several isolated cases of recurrence of severe skin reactions have been reported when treatment with Tolep was restarted. Patients on Tolep therapy who develop a skin reaction should be promptly evaluated and treatment with Tolep should be stopped immediately unless the rash is clearly unrelated to the drug. If treatment is discontinued, consideration should be given to replacing Tolep with another antiepileptic medicinal product to avoid withdrawal attacks. Tolep must not be re-administered in patients who have discontinued treatment due to hypersensitivity reactions (see section 4.3).

Allele HLA-B * 1502 - in the Chinese population of Han ethnicity, Thai and other Asian populations

In individuals of Chinese origin of Han ethnicity and of Thai origin, positivity to the HLA-B * 1502 allele has been shown to be strongly associated with the risk of developing severe skin reactions such as Steven-Johnson syndrome (SJS) during treatment with carbamazepine. The chemical structure of oxcarbazepine is similar to that of carbamazepine, and it is possible that patients who are positive for HLA-B * 1502 may also be at risk of developing SJS after oxcarbazepine treatment. Some data suggest that such an association exists. for oxcarbazepine The prevalence of carriers of the HLA-B * 1502 allele is about 10% in Chinese Han and Thai populations. Allele frequencies of up to about 2% and 6% have been reported in Korea and India, respectively.

Whenever possible, these individuals should be screened for this allele before starting treatment with carbamazepine or chemically related substances. If patients of these origins test positive for the HLA-B * 1502 allele, the use of Tolep can only be considered if the expected benefits outweigh the risks.

Due to the prevalence of this allele in other Asian populations (eg above 15% in the Philippines and Malaysia), testing in genetically at risk populations for the presence of the HLA-B * 1502 allele can be considered.

The prevalence of the HLA-B * 1502 allele is negligible, for example in populations of European origin, African, in a Hispanic population sample and in Japanese (

The presence of the HLA-B * 1502 allele may be a risk factor for the development of SJS / TEN in Chinese patients taking other antiepileptic drugs that can cause SJS / TEN. Therefore, in patients positive for the HLA-B allele * 1502, care should be taken to avoid the use of other drugs that can cause SJS / TEN.

Allele HLA-A * 3101 - in the population of European descent and in the Japanese population

Some data suggest that the HLA-A * 3101 allele is associated with an increased risk of carbamazepine-induced cutaneous adverse reactions including SJS and TEN, rash with eosinophilia (DRESS), or less severe acute generalized exanthematous pustulosis (AGEP) and maculopapular rash in people of European and Japanese descent.

The frequency of the HLA-A * 3101 allele varies widely among ethnic populations. The HLA-A * 3101 allele has a prevalence of 2 to 5% in European populations and approximately 10% in the Japanese population.

The presence of the HLA-A * 3101 allele may increase the risk of carbamazepine-induced skin reactions (mostly less severe) from 5.0% in the general population to 26.0% among subjects of European descent, while its absence can reduce the risk from 5.0% to 3.8%.

There are insufficient data to support the recommendation for screening for HLA-A * 3101 before starting treatment with carbamazepine or chemically related substances.

If patients of European or Japanese descent are found to be positive for the HLA-A * 3101 allele, the use of carbamazepine or chemically related substances should only be considered if the expected benefits outweigh the risks.

Limitations of genetic screening

Genetic screening should never replace "adequate clinical observation and patient management. Many HLA-B * 1502 positive Asian patients treated with Tolep will not develop SJS / TEN and in patients of any ethnicity negative for HLA-B * 1502." HLA-B * 1502 allele, however, episodes of SJS / TEN may occur. Similarly, many patients who are positive for the HLA-A * 3101 allele and treated with Tolep will not develop SJS, TEN, DRESS, AGEP or maculopapular rash, and in patients with any ethnicity negative for the HLA-A * 3101 allele, however, these severe cutaneous adverse reactions may arise.

Hyponatremia

Serum sodium levels below 125 mmol / l, generally asymptomatic and requiring no adjustment of therapy, have been observed in up to 2.7% of patients treated with Tolep. Results from clinical studies show that serum sodium levels return to normal after dose reduction of Tolep, when dosing is stopped or when the patient is treated conservatively (eg by limiting fluid intake). In patients with pre-existing renal dysfunction associated with low sodium levels or in patients treated concomitantly with sodium-lowering drugs (e.g. diuretics, desmopressin) as well as non-steroidal anti-inflammatory drugs (e.g. indomethacin), serum sodium levels should be measured prior to initiation of therapy Serum sodium levels should therefore be measured at approximately two weeks and thereafter at monthly intervals during the first three months of therapy, or as needed clinically.These risk factors may mainly affect elderly patients.

Patients already on Tolep who start treatment with drugs that lower sodium levels should undergo the same checks on serum sodium levels. In general, if symptoms suggestive of hyponatremia occur during Tolep therapy (see section 4.8), measurements of serum sodium levels may be decided. For other patients these tests may be part of the normal laboratory controls.

All patients with heart failure and secondary heart failure should have their weight checked regularly to make sure fluid retention is not occurring. In the event of fluid retention or worsening heart conditions, serum sodium levels should be monitored. If hyponatremia is observed, reducing the fluid intake may represent an "important countermeasure. Since treatment with oxcarbazepine may, in very rare cases, lead to worsening of cardiac conduction, patients with pre-existing conduction disturbances (eg. ventricular, arrhythmia) must be closely monitored.

Liver function

Very rare episodes of hepatitis have been reported, which resolved favorably in most cases. When liver effect is suspected, liver function should be monitored and discontinuation of Tolep therapy considered.

Hematological effects

Very rare cases of agranulocytosis, aplastic anemia and pancytopenia have been reported in patients treated with Tolep post-marketing (see section 4.8).

Discontinuation of treatment should be considered if signs of significant bone marrow depression occur.

Hormonal contraceptives

Patients of childbearing potential should be advised that concomitant use of Tolep and hormonal contraceptives may cancel the effect of the latter (see section 4.5). It is recommended that alternative non-hormonal contraceptive methods be used during Tolep therapy.

Alcohol

Extreme caution is required if alcoholic beverages are consumed while taking Tolep due to the possible additive sedative effect.

Suicidal ideation and behavior

Cases of suicidal ideation and behavior have been reported in patients receiving antiepileptic drugs in their various indications. A meta-analysis of randomized clinical trials versus placebo also highlighted the presence of a modest increase in the risk of suicidal ideation and behavior.

The mechanism of this risk has not been established and the available data do not exclude the possibility of an increased risk with Tolep.

Therefore, patients should be monitored for signs of suicidal ideation and behavior and appropriate treatment should be considered if so. Patients (and caregivers) should be instructed to notify their treating physician if signs of suicidal ideation or behavior emerge.

Discontinuation of treatment

As with other antiepileptic drugs, Tolep treatment should be discontinued gradually to minimize the risk of increased seizure frequency.

04.5 Interactions with other medicinal products and other forms of interaction

Enzyme induction

Oxcarbazepine and its pharmacologically active metabolite (a monohydroxy derivative MHD) are weak inducers in vitro And in vivo of the cytochrome P450 enzymes CYP3A4 and CYP3A5, responsible for the metabolism of many drugs, such as immunosuppressants (e.g. cyclosporine, tacrolimus), oral contraceptives (see below) and some other antiepileptic drugs (e.g. carbamazepine), thus resulting in a decrease in plasma levels of these medicinal products (see the table below which summarizes the interactions with other antiepileptic medicinal products).

In vitro oxcarbazepine and MHD are weak inducers of the UDP-glucuronyl transferase enzyme (effects on specific enzymes belonging to this family are not known). Therefore, in vivo Oxcarbazepine and MHD may have a small inducing effect on the metabolism of medicinal products that are eliminated mainly after conjugation via the UDP-glucuronyl transferase enzyme. When starting treatment or changing the dose of Tolep, the new level of induction can take 2 to 3 weeks.

Upon discontinuation of Tolep therapy, dose reduction of concomitant medicinal products may be required after appropriate clinical evaluation and / or plasma level monitoring. Induction is likely to decrease gradually over 2 to 3 weeks after discontinuation of therapy.

Hormonal contraceptives: Tolep has been shown to affect the two components of an oral contraceptive, ethinylestradiol (EE) and levonorgestrel (LNG). The mean AUC values ​​of EE and LNG decrease by 48-52% and 32-52%. Therefore, concomitant use of Tolep and hormonal contraceptives may render the latter ineffective (see section 4.4). Other methods of contraception, other than hormonal ones, should be considered.

Enzyme inhibition

Oxcarbazepine and MHD inhibit CYP2C19. Therefore, interactions may occur when high doses of Tolep and medicinal products metabolised by CYP2C19 (e.g. phenytoin) are administered concurrently. Plasma levels of phenytoin increase by up to 40% after administration of Tolep at doses greater than 1200 mg / day (see the table below which summarizes the interactions with other antiepileptic medicinal products). In this case, a reduction of the phenytoin dose may be necessary (see section 4.2).

Antiepileptic medicines

Potential interactions between Tolep and other antiepileptic medicinal products were observed during clinical studies. The effect of these interactions on the mean values ​​of AUC and Cmin are summarized in the following table.

Summary of interactions between Tolep and other antiepileptic medicinal products


Co-administered antiepileptic medicinal products Influence of Tolep on other antiepileptic medicinal products Concentration Influence of other antiepileptic medicinal products on MHD Concentration Carbamazepine 0 - 22% decrease (30% increase in the case of carbamazepine-epoxide) 40% decrease Clobazam not studied no influence Felbamato not studied no influence Lamotrigine slight decrease * no influence Phenobarbital 14 - 15% increase decrease of 30 - 31% Phenytoin 0 - 40% increase decrease of 29 - 35% Valproic acid no influence decrease of 0 - 18%

* Preliminary results indicate that oxcarbazepine may lead to decreased lamotrigine concentrations, possibly important in children. However, this potential interaction of oxcarbazepine appears to be less than that observed with the concomitant administration of enzyme-inducing drugs such as carbamazepine, phenobarbital and phenytoin.

The strong inducers of cytochrome P450 enzymes (ie carbamazepine, phenytoin and phenobarbital) are capable of reducing plasma levels of MHD in adults (29-40%); in children aged 4 to 12 years, the clearance of MHD increases by approximately 35% when one of the three enzyme-inducing antiepileptic medicinal products is administered, compared to monotherapy. Concomitant therapy of Tolep and lamotrigine has been associated with an increased risk of adverse events (nausea, somnolence, dizziness and headache). When one or more antiepileptic medicinal products are co-administered with Tolep, cautious dose adjustment and / or monitoring of plasma levels may be necessary as appropriate, especially in pediatric patients concomitantly treated with lamotrigine.

No self-induction phenomena were observed with Tolep.

Interactions with other medicines

Cimetidine, erythromycin, viloxazine, warfarin and dextropropoxyphene have no effect on the pharmacokinetics of MHD.

An interaction between oxcarbazepine and MAO inhibitors is theoretically possible, based on a structural relationship between oxcarbazepine and tricyclic antidepressants.

Patients on tricyclic antidepressant therapy were included in clinical trials and no clinically significant interactions were observed.

Administration of oxcarbazepine and lithium may cause increased neurotoxicity.

04.6 Pregnancy and breastfeeding

Pregnancy

Risks associated with epilepsy and antiepileptic medicines in general:

Patients who may become pregnant or are of childbearing age should be given specialist advice.

The need for antiepileptic treatment should be re-evaluated when the patient plans to become pregnant.

It has been shown that in women born with epilepsy the incidence of malformations is two to three times higher than at a frequency of approximately 3% in the general population. An increase in malformations with polytherapy has not been observed in the population treated. the extent to which treatment is responsible for the disease has been clarified.

Furthermore, effective antiepileptic therapy should not be interrupted, as the aggravation of the disease is harmful to both the mother and the fetus.

Risks associated with oxcarbazepine:

Clinical data on exposure during pregnancy are still insufficient to assess the teratogenic potential of oxcarbazepine. In animal studies, increased incidence of embryo mortality, growth retardation and presence of malformations were observed at maternally toxic doses (see section 5.3).

Taking all this into consideration:

- If patients taking Tolep become pregnant or plan to become pregnant, the use of this product should be carefully re-evaluated. The lowest effective doses should be administered, and monotherapy is preferable, where possible, at least during the first three months of pregnancy. .

- Patients should be advised that the risk of malformations may increase, and should be able to undergo prenatal screening.

- During pregnancy, effective antiepileptic therapy with oxcarbazepine should not be interrupted, as the worsening of the disease is harmful to both the mother and the fetus.

Monitoring and prevention

Antiepileptic medicines can contribute to folic acid deficiency, one of the possible factors responsible for fetal abnormalities. Supplemental administration of folic acid is recommended before and during pregnancy. Since the efficacy of this supplementary administration is not proven, the desirability of a specific prenatal diagnosis may also be considered in women on supplementary treatment with folic acid.

Data from a limited number of women indicate that during pregnancy, due to the physiological changes that occur, the plasma levels of the active metabolite of oxcarbazepine (the monohydroxylated derivative, MHD) may gradually decrease. Therefore, in women undergoing treatment with Tolep during pregnancy, it is recommended that the clinical response be closely monitored and the monitoring of plasma MHD concentrations should be considered to ensure adequate control of seizures during pregnancy. . Monitoring of plasma MHD concentrations may also be considered after delivery, especially if drug doses have been increased during pregnancy.

In the newborn

Bleeding disorders caused by antiepileptic drugs have been reported in newborns. As a precaution, vitamin K1 should be given for preventive purposes during the last weeks of pregnancy, and subsequently to newborns.

Feeding time

Oxcarbazepine and its active metabolite (MHD) are excreted in breast milk. For both compounds the milk / plasma concentration ratio was 0.5. The effects on infants exposed to Tolep in this way are unknown. Therefore Tolep should not be taken during breastfeeding.

04.7 Effects on ability to drive and use machines

The use of Tolep has been associated with the development of undesirable effects such as dizziness and somnolence (see section 4.8). Therefore patients should be warned that their physical and / or mental abilities required to drive or operate machinery could be impaired.

04.8 Undesirable effects

The most commonly reported adverse reactions are somnolence, headache, dizziness, diplopia, nausea, vomiting and fatigue, which occurred in more than 10% of patients.

The undesirable effects described below, by system, refer to adverse events reported in the evaluated clinical studies related to treatment with Tolep. In addition, clinically significant adverse event reports from post-marketing pharmacovigilance and compassionate use programs were reviewed.

Frequency estimate *: Very common: 1/10; Common: 1/100 - ≥ 1/1.000 - ≥ 1/10.000 -

Within each frequency class, undesirable effects are reported in descending order of severity.


Disorders of the blood and lymphatic system Uncommon Leukopenia Very rare Thrombocytopenia Not known Bone marrow depression, aplastic anemia, agranulocytosis, pancytopenia, neutropenia Disorders of the immune system Very rare Hypersensitivity (including multi-organ hypersensitivity) characterized by rash, fever. Other organs or systems may be affected, such as the blood and lymphatic system (e.g. eosinophilia, thrombocytopenia, leukopenia, lymphadenopathy, splenomegaly), the liver (e.g. abnormal liver function test results, hepatitis), muscles and joints (e.g. joint swelling, myalgia, arthralgia), the nervous system (e.g. hepatic encephalopathy), the kidney (e.g. proteinuria, interstitial nephritis, renal failure), the lungs (e.g. dyspnoea, pulmonary edema, asthma, bronchospasm, interstitial lung disease) , angioedema Not known Anaphylactic reactions Metabolism and nutrition disorders common Hyponatremia Very rare Hyponatremia associated with signs and symptoms such as seizures, confusion, altered consciousness, encephalopathy (see also Nervous system disorders for other side effects), visual disturbances (e.g. blurred vision), vomiting, nausea † Not known Hypothyroidism Psychiatric disorders common Confusional state, depression, apathy, agitation (e.g. nervousness), emotional fragility Nervous system disorders Very common Somnolence, headache, dizziness common Ataxia, tremor, nystagmus, impaired concentration, amnesia Eye disorders Very common Diplopia common Blurred vision, visual disturbance Ear and labyrinth disorders common Dizziness Cardiac pathologies Very rare Arrhythmias, atrioventricular block Vascular pathologies Not known Hypertension Gastrointestinal disorders Very common Nausea, vomiting common Diarrhea, constipation, abdominal pain Very rare Pancreatitis and / or increased lipase and / or amylase Hepatobiliary disorders Very rare Hepatitis Skin and subcutaneous tissue disorders common Rash, alopecia, acne Uncommon Urticaria Very rare Angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), erythema multiforme (see section 4.4) Musculoskeletal and connective tissue disorders Very rare Systemic lupus erythematosus General disorders and administration site conditions Very common Fatigue common Asthenia Diagnostic tests Uncommon Elevation of liver enzymes, elevation of blood alkaline phosphatase Not known Decreased T4 levels (with unclear clinical significance)

* based on CIOMS III frequency classification

† Clinically significant hyponatremia (sodium

Adverse reactions from spontaneous reports and literature (frequency not known)

The following adverse reactions derive from post-marketing experience with Tolep and refer to spontaneous reports and cases described in the literature. As these reactions arise spontaneously from a population of uncertain size, it is not possible to estimate with certainty the frequency which is therefore indicated. as “not known.” Adverse reactions are listed by MedDRA system organ class. Within each class, adverse reactions are listed in order of decreasing severity.

Disorders of the immune system

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS).

Skin and subcutaneous tissue disorders

Acute Generalized Exanthematous Pustulosis (AGEP).

Musculoskeletal and connective tissue disorders

There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with Tolep. The mechanism by which Tolep affects bone metabolism has not been identified.

04.9 Overdose

Isolated cases of overdose have been reported. The maximum dose taken was approximately 24,000 mg. All patients recovered with symptomatic treatment alone. Symptoms of overdose include somnolence, dizziness, nausea, vomiting, hyperkinesia, hyponatremia, ataxia and nystagmus. There is no specific antidote.Patients with symptoms of poisoning due to an overdose of Tolep should be treated with appropriate symptomatic and supportive therapy, and the drug should optionally be removed by gastric lavage and / or inactivated by administration of activated charcoal.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiepileptic, derivative of carboxamide, ATC code: N03AF02

The active substance in Tolep, oxcarbazepine, and its 10-monohydroxylated metabolite exert an antiepileptic effect.

Both active ingredients have been shown to be potent and effective anticonvulsants in a series of animal pharmacological studies.

Furthermore, in the "rabid cat" model, the results obtained are indicative of a potential psychotropic effect in humans.

Animal studies, which concern the spectrum of activity of oxcarbazepine, indicate particular efficacy in partial and generalized tonic-clonic seizures.

The anticonvulsant mechanism of action of oxcarbazepine and its main metabolite has only been partially elucidated; however, it is believed that, similar to carbamazepine, these substances stabilize over-excited neuronal membranes, inhibit repetitive neuronal discharges and the transmission of synaptic impulses.

The active substance of Tolep does not show self-induction: the pharmacokinetics of oxcarbazepine and its pharmacologically active metabolite do not change after repeated administration. Furthermore, in clinical and pharmacokinetic studies, oxcarbazepine was found to have a lower enzyme induction potential than that of carbamazepine.

No Tolep influence on the EEG trace is evident.

Tolep is suitable both as monotherapy and in combination with other antiepileptics (e.g. valproate, phenytoin).

05.2 Pharmacokinetic properties

Absorption

Rapid and practically complete absorption, at most 95%.

Plasma concentration: due to rapid metabolism, the plasma concentration of oxcarbazepine is negligible and the pharmacologically active metabolite (10-hydroxy-10,11-dihydro-5-carbamoyl-5H-dibenzazepine = 10-monohydroxy derivative) predominates.

After single oral doses of 150-600 mg oxcarbazepine, the plasma AUC of the 10-monohydroxy metabolite shows a linear correlation with the administered dose.

In patients with epilepsy, daily doses of oxcarbazepine ranging from 600 to 5400 mg produce steady-state plasma concentrations of the active metabolite ranging from 2.1 to 36.7 μg / ml. The plasma peaks of the active metabolite are reached, after single administration, within 4 hours. The pharmacokinetics of oxcarbazepine and its active metabolite remain unaltered even after repeated oral administration.

In children, steady-state concentrations are comparable to those in adults.

Distribution

Volume of distribution: 0.8 l / kg (active metabolite).

Protein binding: 38% (active metabolite).

Metabolism

Oxcarbazepine is rapidly largely reduced to its pharmacologically active metabolite, the 10-monohydroxy derivative (present both free and conjugated, accounting for about 60% of the compounds excreted by the kidney).

Minor metabolites: direct glucuronide and sulfate of oxcarbazepine and metabolite 10,11-dihydroxy (approximately 5-15% each). Unchanged oxcarbazepine: less than 0.3%.

Elimination

Complete elimination within 10 days. More than 95% of the administered dose is excreted in the urine, mostly in the form of metabolites; about 3% with feces.

Elimination half-life 8-13 hours (active metabolite).

05.3 Preclinical safety data

Preclinical data obtained from repeated dose toxicity, pharmacological safety and genotoxicity studies conducted with oxcarbazepine and its pharmacologically active metabolite (monohydroxylated derivative, MHD), revealed no special hazard for humans.

Signs of nephrotoxicity were observed in repeat-dose studies conducted in rats, but not in mice and dogs. Since similar effects have not been reported in humans, the clinical significance of these findings in the rat remains unknown.

Immunostimulation tests conducted in mice showed that MHD (and to a lesser extent oxcarbazepine) can induce delayed hypersensitivity.

Animal studies have revealed, at maternally toxic doses, an increase in the incidence of embryonic mortality and sometimes ante and / or postnatal growth retardation. In one of eight embryonic toxicity studies performed with both oxcarbazepine and its pharmacologically active metabolite (MHD), an increase in fetal malformations in the rat occurred at doses that were also maternal toxic (see section 4.6).

In carcinogenicity studies, tumors of the liver (rat and mouse), testes and granular cells of the female genital tract (rat) were induced in treated animals. The appearance of liver tumors was most likely a consequence of the induction of hepatic microsomal enzymes, an inductive effect which, although it cannot be excluded, is weak or absent in patients treated with Tolep. Testicular tumors may have been induced by high concentrations of luteinizing hormone. Since this increase is not found in humans, these tumors are thought to be of no clinical relevance. In the carcinogenicity study conducted with MHD in rats, a dose-related increase in the incidence of granular cell tumors of the female genital tract (cervix and vagina) was observed. These effects occurred at exposure levels comparable to those expected in practice. The mechanism of development of these tumors has not been elucidated, therefore the clinical significance of these tumors is not known.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Colloidal anhydrous silica, microcrystalline cellulose, hypromellose, red iron oxide, yellow iron oxide, magnesium stearate, carmellose sodium.

06.2 Incompatibility

None known.

06.3 Period of validity

3 years.

06.4 Special precautions for storage

This medicine does not require any special storage conditions.

06.5 Nature of the immediate packaging and contents of the package

Non-toxic PVC or PVC / PCTFE blisters

Box of 50 divisible tablets of 300 mg.

Box of 50 divisible tablets of 600 mg.

06.6 Instructions for use and handling

No special instructions.

07.0 MARKETING AUTHORIZATION HOLDER

Novartis Farma S.p.A.

Largo Umberto Boccioni, 1 - 21040 Origgio (VA)

08.0 MARKETING AUTHORIZATION NUMBER

TOLEP 300 mg tablets - 50 divisible tablets A.I.C. n .: 028304018

TOLEP 600 mg tablets - 50 divisible tablets A.I.C. n .: 028304020

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

First authorization: 31.10.1994

Renewal: 15.11.2009

10.0 DATE OF REVISION OF THE TEXT

AIFA determination of 04.04.2014

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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